JPH0764808B2 - Novel 9-halogen prostaglandins and their manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to (5Z, 13E)-(9R, 11R, 15S) -9-halogen-
15-cycloalkyl-11,15-dihydroxy-16,17,18,
The present invention relates to a 19,20-pentanol-5,13-prostadienoic acid derivative, a physiologically acceptable salt thereof and a clathrate thereof, a method for producing the same and a pharmaceutical composition containing the same.

German Patent Publication Nos. 2950027 and 312
No. 6924 has the following formula: [In the formula, Hal represents fluorine or chlorine, and R ₁ represents a CH ₂ OH group or (R ₂ is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group), or R ₁ is (R ₃ is an acid group or R ₂ group), and A is —CH ₂ —CH ₂
- group or a cis -CH = CH- group, B is -CH ₂ -CH ₂ -
Represents a radical or trans-CH = CH-group or -C≡C-group, W represents a free or functionalized hydroxymethylene group, wherein the OH-group is in the α-position or the β-position. D and E may together represent a direct bond, or D may represent a straight-chain or branched alkylene radical having 1 to 10 carbon atoms, optionally substituted by a fluorine atom. is may have, E is an oxygen atom or a sulfur atom, a direct bond, -C≡C- bond or -CR ₆ = CR ₇ - represents a group, where R ₆ and R ₇ are different, a hydrogen atom, a chlorine atom Or an alkyl group, R ₄ represents a free or functionalized hydroxy group, R ₅ represents a hydrogen atom, an alkyl group, a halogen-substituted alkyl group, a cycloalkyl group, or optionally substituted. Representing an aryl group or heterocyclic group] Derivatives, as well as salts with physiologically acceptable bases when R ₂ represents a hydrogen atom, are claimed.

German Patent Publication Nos. 2950027 and 312
The prostaglandin derivatives from 6924 are suitable for inducing menstruation or aborting pregnancy with a single intestinal or parenteral administration. This is a female mammal such as a rabbit,
It is suitable for sexual cycle synchronization in cattle, horses or pigs and for cervical dilation as a diagnostic or therapeutic pretreatment.

This compound suppresses gastric acid secretion and exhibits cytoprotective and ulcer healing effects, thus blocking the unwanted consequences of non-steroidal anti-inflammatory substances.

In addition, some of these compounds have blood pressure lowering, cardiac arrhythmia regulating and antiplatelet activity.

9-halogen-15-cycloalkylprostaglandin derivatives are also described in German patent application DE 2950027 A1 and German patent application DE 3126924 A1.
No name is given in the specification, and the compound exhibits a pharmacological action different from that of the compounds obtained from the above-mentioned specifications (this will be further described later).

Accordingly, the present invention provides Formula I: [Wherein R ₁ represents hydrogen or methyl, R ₂ represents fluorine or chlorine, n is 0 or 1], and R ₁ is hydrogen. Represents a salt with a physiologically acceptable base or its cyclodextrin clathrate.

The alkyl group R _3, a straight-chain and branched-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl, isopentyl, and hexyl. Preferred groups are methyl, ethyl, propyl and isopropyl.

For salt formation, inorganic and organic bases known to those skilled in the art to produce physiologically acceptable salts are suitable. For example, alkali hydroxides such as sodium and potassium hydroxide, alkaline earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris- (hydroxymethyl).
-Methylamine and the like.

The present invention further provides Formula II, [Wherein the OH-group may be in the α-position or the β-position, R ₁ represents methyl, n represents the above-mentioned, THP represents tetrahydropyranyl] and the intermediate 9-sulfone Formula III: R ₃ -Hal (wherein R ₃ represents lithium, sodium or potassium when Hal is chlorine, and R ₃ is tetra- (C _1-) when Hal is fluorine. C ₆ −
Alkyl) -ammonium], optionally liberating the protected hydroxy groups in any order in the reaction product obtained and then saponifying the esterified carboxyl groups (R ₁ ═CH ₃ ). And / or a process for the preparation of 9-halogen-15-cycloalkylprostaglandin derivatives of the formula I characterized by converting the free carboxyl groups (R ₁ = H) into salts or clathrates.

The conversion of compounds of general formula II into 9-sulphonic acid esters is carried out in a manner known per se using alkylsulphonyl chlorides or arylsulphonyl chlorides, for example in the presence of amines such as pyridine or triethylamine, at -60 ° C.
It is carried out at temperatures of ˜ + 100 ° C., preferably −20 ° C. to + 50 ° C. The nucleophilic displacement of the 9-sulfonate by chlorine atoms is with alkali chloride, preferably lithium chloride, and the substitution with fluorine atoms is tetra- (C ₁ -C ₆ -alkyl) -ammonium fluoride, preferably tetra. Butyl ammonium fluoride at 0 ° C in an inert solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, dimethoxyethane, tetrahydrofuran, etc.
It is carried out at temperatures of -100 ° C, preferably 20 ° C-80 ° C.

Decomposition of the tetrahydropyranyl group can be carried out, for example, by oxalic acid, acetic acid,
It is carried out in an aqueous solution of an organic acid such as propionic acid or the like or in an aqueous solution of an inorganic acid such as hydrochloric acid. To improve solubility it is advantageous to add an inert organic solvent which is miscible with water. Suitable organic solvents are, for example, alcohols such as methanol and ethanol, and ethers such as dimethoxyethane, dioxane and tetrahydrofuran. Preference is given to using tetrahydrofuran. The decomposition is preferably carried out at temperatures between 20 ° C and 80 ° C.

The prostaglandin derivatives of formula I in which R ₁ represents a hydrogen atom can be converted into the salt under neutralization with the appropriate amount of the corresponding inorganic base. If, for example, the corresponding PG-acid is dissolved in water containing a stoichiometric amount of base, a solid inorganic salt is obtained after evaporation of the water or after addition of a water-miscible solvent such as alcohol or acetone.

For the conventional preparation of amine salts, the PG-acid is dissolved in a suitable solvent such as ethanol, acetone, diethyl ether, acetonitrile or benzol and at least a stoichiometric amount of amine is added to this solution. In this case, the salt usually occurs as a solid or is separated off after evaporation of the solvent by customary methods.

To produce a clathrate, a compound of formula I is dissolved in a pharmacologically harmless alcohol, preferably ethanol,
Add to an aqueous solution of α-, β- or γ-cyclodextrin, especially β-cyclodextrin at 60 ° C. After cooling, the corresponding clathrate crystallizes out and can be isolated as solid free-flowing crystals by suction filtration and drying.

The starting compound of formula II is published in German Patent Application No. 25
No. 15770.

The 15-cycloalkylprostaglandins according to the invention of the formula I are characterized by the properties of the PGD ₂ type. That this compound PGD ₂ - well bound to the receptor, whereas PGE ₂ -
And PGI ₂ -receptor is difficult to bind. Examination of bovine coronary arteries and rabbit pulmonary arteries also revealed that PG of the compound of formula I
D ₂ − shows the working outline.

These compounds have hypotensive effects when injected intravenously into rats.

The active substances according to the invention suppress the secretion of gastric acid and show cytoprotective and ulcer healing effects, thus blocking the undesired consequences of non-steroidal anti-inflammatory substances (prostaglandin synthesis-inhibitors). This substance has a cardiac arrhythmia regulating action and a platelet coagulation inhibiting action.

For inhalation of these active substances for use as a medicine,
It may also be adapted into a form suitable for oral, parenteral or topical (eg vaginal) administration.

For inhalation it is preferred to make an aerosol solution.

For oral administration, tablets, dragee pills or capsules are suitable, for example.

For parenteral application, sterile, injectable aqueous or oil solutions are used.

For example, cones are suitable and common for vaginal application.

The invention therefore also relates to medicaments based on the compounds of the general formula I which consist of conventional adjuvants and excipients.

The active substances according to the invention are known for crude drugs and can be used in combination with conventional adjuvants, for example in the manufacture of pharmaceutical preparations. The formulations may contain 0.01 to 50 mg of active compound.

The present invention is described in more detail by the following examples, but the present invention is not limited thereto.

Example 1 (5Z, 13E)-(9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanol-5,13-prostadienoic acid Methyl ester (5Z, 13E)-(9S, 11R, 15S) -15-cyclohexyl-9-hydroxy-11,15-bis (tetrahydropyran-2-yloxy) -16,17,18,19, in 10 ml of pyridine. 20-Pentanol-5,13-prostadienoic acid methyl ester 1.
To 098 g of solution at 0 ° C. p-toluenesulfonic acid chloride
Add 191 mg and after 24 hours add another 191 mg. Let stand at 0 ° C for a total of 48 hours, then add 0.1 ml of water, stir for 2 hours, dilute with 200 ml of ether, wash successively with dilute sulfuric acid, water and brine, dry over magnesium sulfate and evaporate. 1.20 g of 9α-tosylate are obtained as a colorless oil.

_{IR (CHCl 3): 2945,2872,1735,1366,1240,978 /} cm.

1.05 g of 9α-tosylate in 45 ml of dimethylformamide
Is stirred with 600 mg of lithium chloride at 65 ° C. for 4 hours.
Dilute with brine and extract with ether / hexane (1: 1),
The extracts are washed with water and brine, dried over magnesium sulphate and evaporated in vacuo. The residue is purified by chromatography on silica gel with toluene / ethyl acetate (95: 5-80: 20). 9β-Chlorine compound
520 mg are obtained which are stirred for 18 hours at 32 ° C. with 20 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) in order to separate the tetrahydropyranyl ether protecting groups. After evaporating the solution in vacuo, the residue is chromatographed on silica gel. 285 mg of the title compound are obtained as a colorless oil with dichloromethane-acetone (9: 1) as eluent.

IR (CHCl ₃ ): 3600, 3410, 3000, 2932, 2859, 1732, 97
2 / cm.

Example 2 (5Z, 13E)-(9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanol-5,13-prostadienoic acid 220 mg of the methyl ester obtained according to Example 1 are stirred with a solution of 100 mg of potassium hydroxide, 0.5 ml of water and 5 ml of ethanol at 20 ° C. for 5 hours. Evaporate in vacuo, dilute with 20 ml of water, adjust to pH 4 with citric acid and extract with dichloromethane. The extracts are washed with water, dried over magnesium sulphate and evaporated in vacuo. The residue is purified by chromatography on silica gel. Elution with dichloromethane-methanol (95: 5). 192 mg of the title compound are obtained as a colorless oil.

_{IR (CHCl 3): 3600,3450,2955,2859,1710,974 /} cm.

Example 3 (5Z, 13E)-(9R, 11R, 15S) -9-chloro-15-cyclopentyl-11,15-dihydroxy-16,17,18,19,20-pentanol-5,13-prostadienoic acid Methyl ester (5Z, 13E)-(9S, 11R, 15S) -15-cyclopentyl-9
-Hydroxy-11,15-bis (tetrahydroparan-2
-Yloxy) -16,17,18,19,20-pentanol-5,13
Starting from 1.05 g of methyl prostadienoic acid,
Process as described in Example 1. 242 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 3600, 3405, 2998, 2935, 2858, 1735, 97
8 / cm.

Example 4 (5Z, 13E)-(9R, 11R, 15S) -9-chloro-15-cyclopentyl-11,15-dihydroxy-16,17,18,19,20-pentanol-5,13-prostadienoic acid 180 mg of the methyl ester obtained according to Example 3 were saponified by the method described in Example 2 to give 135 m of the title compound as an oil.
g is obtained.

_{IR (CHCl 3): 3600,3450,2927,2860,1709,976 /} cm.

Example 5 (5Z, 13E)-(9R, 11R, 15S) -15-cyclohexyl-1
1,15-dihydroxy-9-fluoro-16,17,18,19,20-
Pentanol-5,13-prostadienoic acid methyl ester (5Z, 13E)-(9S, 11R, 1 in 70 ml of dimethyl sulfoxide
5S) -15-Cyclohexyl-9-tosyloxy-11,15
-Bis (tetrahydropyran-2-yloxy) -16,1
To a solution of 4.2 g of 7,18,19,20-pentanol-5,13-prostadienoic acid methyl ester (prepared according to Example 1), tetrabutylammonium fluoride (distilled with toluene in vacuum at 50 ° C. multiple times) 12 g), and stirred under argon at 22 ° C. for 2 hours. Water 400m
Dilute with l and extract 3 times with 150 ml of ether / hexane (2: 1) each time, wash the extract with brine, dry over magnesium sulphate and evaporate in vacuo. The residue was purified on silica gel, eluting with 9β-fluorine compound (1.03 g) in hexane-ethyl acetate (10: 1), and at 1 ° C at 22 ° C for separation of protecting groups.
Stir for 8 hours with 25 ml of a mixture consisting of acetic acid-water-tetrahydrofuran (65/35/10). After evaporation of the solution and chromatographic purification on silica gel with dichloromethane-acetone (10: 1), 830 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 3600, 3410, 2998, 2932, 2865, 1729, 97
6 / cm.

Example 6 (5Z, 13E)-(9R, 11R, 15S) -15-cyclohexyl-1
1,15-dihydroxy-9-fluoro-16,17,18,19,20-
Pentanol-5,13-prostadienoic acid The methyl ester prepared in Example 5 treated according to Example 2 500 m
425 mg of the title compound are obtained as a colorless oil from g.

_{IR (CHCl 3): 3600,3405,2930,2858,1710,976 /} cm.

Example 7 (5Z, 13E)-(9R, 11R, 15S) -15-cyclopentyl-1
1,15-dihydroxy-9-fluoro-16,17,18,19,20-
Pentanol-5,13-prostadienoic acid methyl ester (5Z, 13E)-(9S, 11R, 15S) -15-cyclopentyl-9-hydroxy-11,15-bis (tetrahydropyran-2-yloxy) in 10 ml of pyridine ) -16,17,18,19,20-Pentanol-5,13-prostadienoic acid methyl ester 1.
1 g of p-toluenesulfonic acid chloride was added to 07 g of solution at 0 ° C.
Add 91 mg, stir at 0 ° C. and after 24 hours add more 191 mg of acid chloride. After 48 hours, add 0.1 ml of water, stir for 2 hours, dilute with ether, wash successively with dilute sulfuric acid, water and brine, dry over magnesium sulfate and evaporate to give 9α-tosylate as a colorless oil 1.12 g. Is obtained.

_{IR (CHCl 3): 2952,2878,1733,1359,1241,976 /} cm.

To a solution of 1 g of 9α-tosylate in 20 ml of dimethylsulfoxide is added 3 g of tetrabutylammonium fluoride, stirred for 2 hours at room temperature, then diluted with water and then extracted several times with ether / hexane (2: 1). The combined extracts are washed with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by silica gel and eluted with 205 mg of 9β-fluorine compound with hexane-ethyl acetate (85:15),
To remove the protecting groups, stir at room temperature for 18 hours with 5 ml of a mixture of acetic acid-water-tetrahydrofuran (65/35/10). After evaporation of the solution and chromatographic purification on silica gel with dichloromethane-acetone (85:15), 110 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 3600, 3408, 2998, 2929, 2854, 1733, 97
6 / cm.

Example 8 (5Z, 13E)-(9R, 11R, 15S) -15-cyclopentyl-1
1,15-dihydroxy-9-fluoro-16,17,18,19,20-
Pentanol-5,13-prostadienoic acid 85 mg of the methyl ester prepared in Example 7 in 5 ml of ethanol.
50 mg of potassium hydroxide dissolved in 0.5 ml of water was added to the solution of 2.
Stir at 0 ° C. for 5 hours. After evaporation in a vacuum, 10 ml of water are added, acidified to pH 3 with citric acid, extracted several times with dichloromethane, dried over magnesium sulphate and evaporated in a vacuum. 72 mg of the title compound are obtained as a colorless oil.

_{IR (CHCl 3): 3600,3430,2931,2859,1710,974 /} cm.

Example 9 (5Z, 13E)-(9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanol-5,13-prostadienoic acid Tris (hydroxymethyl) -aminomethane salt of (5Z, 13E)-(9R, 11R, 15S)-in 40 ml of acetonitrile-
A solution of 250 mg of 9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanol-5,13-prostadienoic acid in tris (hydroxymethyl) in 0.25 ml of water at 65 ° C. ) -A solution of 75 mg of aminomethane is added. Cool to 20 ° C. with stirring and filter off the solvent with suction. 205 mg of the title compound which crystallizes is obtained. Melting point 118-120
° C.

IR (KBr): 2965, 1655, 1420, 976 / cm.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Rogue, Olaf Germany 1000 Berlin 27, Bekasinenwäk 37 (72) Inventor Schiller, Etzkehardt Germany 1000 Berlin 28, Im Amseltal 50

Claims (7)

[Claims] 1. Formula I: 9-halogen-15 in which R ₁ represents hydrogen or methyl, R ₂ represents fluorine or chlorine, and n represents 0 or 1.
A cycloalkyl prostaglandin derivative and, where R ₁ represents hydrogen, a salt with a physiologically acceptable base or its cyclodextrin clathrate. 2. (5Z, 13E)-(9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,1
The compound of claim 1 which is 8,19,20-pentanol-5,13-prostadienoic acid. 3. (5Z, 13E)-(9R, 11R, 15S) -9-chloro-15-cyclopentyl-11,15-dihydroxy-16,17,1
The compound of claim 1 which is 8,19,20-pentanol-5,13-prostadienoic acid. 4. (5Z, 13E)-(9R, 11R, 15S) -15-cyclohexyl-11,15-dihydroxy-9-fluor-16,1
A compound according to claim 1 which is 7,18,19,20-pentanol-5,13-prostadienoic acid. 5. (5Z, 13E)-(9R, 11R, 15S) -15-Cyclopentyl-11,15-dihydroxy-9-fluor-16,1
A compound according to claim 1 which is 7,18,19,20-pentanol-5,13-prostadienoic acid. 6. (5Z, 13E)-(9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,1
The compound according to claim 1, which is a tris (hydroxymethyl) -aminomethane salt of 8,19,20-pentanol-5,13-prostadienoic acid. 7. Formula I: 9-halogen-15 in which R ₁ represents hydrogen or methyl, R ₂ represents fluorine or chlorine, and n represents 0 or 1.
-A method for preparing a cycloalkyl prostaglandin derivative, wherein formula II: [Wherein the OH-group may be in the α- or β-position, R ₁ represents methyl, n represents the above and THP represents tetrahydropyranyl], and the intermediate 9-sulfonic acid Via the ester, the formula III: R ₃ -Hal [wherein R ₃ represents lithium, sodium or potassium when Hal is chlorine, and R ₃ is tetra- (C ₁ -C ₁ when Hal is fluorine). ₆ −
Alkyl) -representing ammonium], optionally releasing the protected hydroxy groups in any order in the resulting reaction product, saponifying the esterified carboxyl groups (R ₁ = CH ₃ ), and A method for producing a 9-halogen-15-cycloalkyl-prostaglandin derivative, which comprises converting a free carboxyl group (R ₁ = H) into a salt or a clathrate.